Aarhus University Seal

Seandean Lykke Harwood: Investigation of the protease inhibitor α2-macroglobulin using mass spectrometry

PhD defence, Tuesday, 27 April 2021. Seandean Lykke Harwood

Seandean Lykke Harwood
Figure 1. A putative model of A2M’s protease-inhibiting mechanism.

During his industrial PhD with Novo Nordisk as the industrial partner, Seandean Lykke Harwood developed methods using modern mass spectrometry towards protein characterization. The model protein chosen for applying these methods was ?2-macroglobulin (A2M), a protease inhibitor found in the blood of most animals which has a long history at the Molecular Biology & Genetics department.

These studies have uncovered new aspects of A2M’s structure and function (Figure 1) and suggested ways in which A2M might be engineered towards therapeutic applications.

Structural investigations of A2M in its native conformation and in complex with proteases were used to develop a model for A2M’s inhibitory mechanism. Up to two proteases are able to enter A2M’s hollow interior, where they can access and cleave A2M’s bait regions.

This triggers a conformational change in A2M which traps the proteases, preventing them from cleaving other proteins. The methods on which these models were based included negative stain electron microscopy, small angle x-ray scattering, and cross-linking mass spectrometry.  

The PhD study was completed at Molecular Biology & Genetics, Faculty of Natural Sciences, Aarhus University.

This summary was prepared by the PhD student.

The PhD defence will be held online. To receive a link to the event, please send an e-mail to Jan J. Engild at jje@mbg.au.dk.

Title of PhD thesis: ?2-macroglobulin: Investigation of its native conformation, bait region, and thiol ester using mass spectrometry and mutant characterization
Contact information: Seandean Lykke Harwood, e-mail: sdlh@mbg.au.dk, tel.: +45 23 72 37 66
Members of the assessment committee:
Michael Toft Overgaard, Professor, Department of Chemistry and Bioscience, Aalborg University
Amy Wyatt, Senior Lecturer, Flinders Medical Centre, Flinders University, Australia
Jan Trige Rasmussen, Senior Researcher, Department of Molecular Biology & Genetics, Aarhus University
Main supervisor:
Professor Jan J. Enghild, Department of Molecular Biology & Genetics, Aarhus University
Dr. Peter Kresten Nielsen, MS Characterisation, Novo Nordisk
Language: The PhD dissertation will be defended in English

The defence is public.
Due to the coronavirus situation, the PhD thesis will not be available for reading at the offices of the PhD administration. Instead, interested parties may send an e-mail to gradschool.nat@au.dk to receive a digital copy of the PhD thesis. Please note, it may in certain cases be necessary to make an individual arrangement to read the PhD thesis.